| Autor: |
Altenbach, R. J., Khilevich, A., Kolasa, T., Rohde, J. J., Bhatia, P. A., Patel, M. V., Searle, X. B., Yang, F., Bunnelle, W. H., Tietje, K., Bayburt, E. K., Carroll, W. A., Meyer, M. D., Henry, R., Buckner, S. A., Kuk, J., Daza, A. V., Milicic, I. V., Cain, J. C., Kang, C. H., Ireland, L. M., Carr, T. L., Miller, T. R., Hancock, A. A., Nakane, M., Esbenshade, T. A., Brune, M. E., O'Neill, A. B., Gauvin, D. M., Katwala, S. P., Holladay, M. W., Brioni, J. D., Sullivan, J. P. |
| Zdroj: |
Journal of Medicinal Chemistry; June 2004, Vol. 47 Issue: 12 p3220-3235, 16p |
| Abstrakt: |
Structure−activity studies were performed on the α1A-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the α1A, α1b, α1d, α2a, and α2B subtypes. Functional activity in tissues containing the α1A (rabbit urethra), α1B (rat spleen), α1D (rat aorta), and α2A (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the α1A-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective α1-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater α1A selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the α1A-AR subtype in the control of MAP. |
| Databáze: |
Supplemental Index |
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